TY - JOUR
T1 - Genomic spectra of biliary tract cancer
AU - Nakamura, Hiromi
AU - Arai, Yasuhito
AU - Totoki, Yasushi
AU - Shirota, Tomoki
AU - Elzawahry, Asmaa
AU - Kato, Mamoru
AU - Hama, Natsuko
AU - Hosoda, Fumie
AU - Urushidate, Tomoko
AU - Ohashi, Shoko
AU - Hiraoka, Nobuyoshi
AU - Ojima, Hidenori
AU - Shimada, Kazuaki
AU - Okusaka, Takuji
AU - Kosuge, Tomoo
AU - Miyagawa, Shinichi
AU - Shibata, Tatsuhiro
N1 - Funding Information:
This study was supported by Grants-in-Aid from the Ministry of Health, Labour and Welfare and the Japan Agency for Medical Research and Development (Health and Labour Sciences Research Expenses for Commission and Applied Research for Innovative Treatment of Cancer), National Cancer Center Research and Development Funds (26-A-5), MEXT KAKENHI (grant 26461040) and the Yasuda Medical Foundation. The National Cancer Center Biobank is supported
Funding Information:
by the National Cancer Center Research and Development Fund, Japan. The supercomputing resource ‘SHIROKANE’ was provided by the Human Genome Center, The University of Tokyo.
Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
PY - 2015/8/27
Y1 - 2015/8/27
N2 - The incidence of biliary tract cancer (BTC), including intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and gallbladder cancer, has increased globally; however, no effective targeted molecular therapies have been approved at the present time. Here we molecularly characterized 260 BTCs and uncovered spectra of genomic alterations that included new potential therapeutic targets. Gradient spectra of mutational signatures with a higher burden of the APOBEC-associated mutation signature were observed in gallbladder cancer and ECC. Thirty-two significantly altered genes, including ELF3, were identified, and nearly 40% of cases harbored targetable genetic alterations. Gene fusions involving FGFR2 and PRKACA or PRKACB preferentially occurred in ICC and ECC, respectively, and the subtype-associated prevalence of actionable growth factor-mediated signals was noteworthy. The subgroup with the poorest prognosis had significant enrichment of hypermutated tumors and a characteristic elevation in the expression of immune checkpoint molecules. Accordingly, immune-modulating therapies might also be potentially promising options for these patients.
AB - The incidence of biliary tract cancer (BTC), including intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and gallbladder cancer, has increased globally; however, no effective targeted molecular therapies have been approved at the present time. Here we molecularly characterized 260 BTCs and uncovered spectra of genomic alterations that included new potential therapeutic targets. Gradient spectra of mutational signatures with a higher burden of the APOBEC-associated mutation signature were observed in gallbladder cancer and ECC. Thirty-two significantly altered genes, including ELF3, were identified, and nearly 40% of cases harbored targetable genetic alterations. Gene fusions involving FGFR2 and PRKACA or PRKACB preferentially occurred in ICC and ECC, respectively, and the subtype-associated prevalence of actionable growth factor-mediated signals was noteworthy. The subgroup with the poorest prognosis had significant enrichment of hypermutated tumors and a characteristic elevation in the expression of immune checkpoint molecules. Accordingly, immune-modulating therapies might also be potentially promising options for these patients.
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U2 - 10.1038/ng.3375
DO - 10.1038/ng.3375
M3 - Article
C2 - 26258846
AN - SCOPUS:84940556535
SN - 1061-4036
VL - 47
SP - 1003
EP - 1010
JO - Nature genetics
JF - Nature genetics
IS - 9
ER -
